Over the past few years, significant research has been directed toward the development of new technologies for environmentally benign processes (e.g., green chemistry), which are both economically and technologically feasible. One important area of green chemistry deals with solvent minimization.
Solvent minimization processes are those conducted in minimal amount of solvent or conducted in solvent-free environments. Solvent-free environments generally exhibit the high efficiency, while eliminating the costs of processing, handling and disposal of the solvent. Limited success has been achieved with solvent minimization processes employing aqueous systems, ionic liquids, immobilized solvents, dendrimers, amphiphilic star polymers or supercritical fluids. The major challenge encountered in solvent minimization processes is the lack of a common phase (e.g., the solvent medium) that brings the reactants into closer proximity.
Solvent minimization processes are especially desired in the manufacture of certain compounds used as active ingredients in pharmaceuticals. Examples of the solvent processes to synthesize N-acetyl-p-aminophenol (acetaminophen, sold under the trademark Tylenol®) are the Mallinckrodt Process, Celanese Process, Sterling Process and Monsanto Process, known to those with ordinary skill in the art.
For example, the Monsanto Process is described in U.S. Pat. Nos. 3,334,587 and 3,076,030, both of which are herein incorporated herein by reference, as well as the Sterling Process. The p-nitrophenol is reduced to p-aminophenol and then acetylated to render N-acetyl-p-aminophenol. Unfortunately, the processes of the prior art require the use of undesirable solvents.
In the Celanese Process, as described in U.S. Pat. No. 4,954,652, incorporated herein by reference, N-acetyl-para-aminophenol is prepared by subjecting 4-hydroxyacetophenone oxime to a Beckman rearrangement in the presence of a thionyl chloride catalyst and an alkyl alkanoate as the reaction solvent. Like the other processes of the prior art, the Celanese Process requires the use of an organic solvent.
Since acetaminophen is the most prescribed analgesic in the world because of its antipyretic activity, a solvent minimized process is desired. Some success has been achieved in co-pending U.S. patent application Ser. No. 10/666,543, entitled “Method of Producing Organic Compounds in Presence of Oxyethylene Ether Catalyst and in a Solvent Minimized Environment,” which is assigned to a common assignee and incorporated herein by reference. A corollary publication is Bhattacharya, A.; Purohit, V.; Rinaldi, F. Org. Proc. Res. Dev. 2003, 7, 254, also incorporated herein by reference. In at least one embodiment, the application discloses a simple and highly efficient potassium thioacetate mediated one-pot conversion of aryl nitro compounds to aryacetamides. The reactions are conducted by employing potassium thioacetate (4 eq.) as a nucleophile in dipolar aprotic solvents such as DMF or in a solvent-free environment in presence of catalytic amounts of polyethylene glycol (PEG) type surfactants such as Triton-X. Further, crownether-like complementary nature of the various types of Triton-X and its differential solubilization tendencies for specific counterions has been demonstrated. Rebeck, J. Angew. Chem. Int. Ed. Engl. 1990, 29, 245. March, J. Adv. Org. Chem. 4th Ed. John Wiley, 82–93 and references cited therein.
Although the acetamidation proceeds well with useful level of conversion and efficiency in the above referenced patent application, its utility is limited by the use of large amount of relatively expensive potassium thioacetate. The process is also encumbered by undesirable amounts of salt-waste formation leading to complex isolation as well as higher disposal cost. Furthermore, use of stoichiometric amounts of the highly nucleophilic thioacetate anion is associated with unwanted nucleophilic displacement of halogen in the aromatic system.
Aryl amides have been demonstrated to be versatile and useful synthetic intermediate and are important structural elements of several drugs and candidates.1 Traditional two-step syntheses of N-arylacetamides involving reduction of nitroarenes to N-arylamines followed by acylation to the corresponding N-arylacetamides employing activated carboxylic acids are well documented. Accordingly, a variety of methods for the reduction of nitro groups to amines using various metal catalysts, such as platinum oxide, rhodium-platinum oxide, palladium, Raney Ni, copper, ruthenium sulfide, zinc and iron as well as samarium, indium, or Bakers' yeast have been developed. See, e.g. Nishimura, S. Bull. Chem. Soc. Jpn. 1961, 34, 32. Adams, R.; Cohen, F. L. Org. Syn. Coll. 1932, 1, 240. Mendennhall, G. D.; Smith, P. A. S. Org. Syn. Coll. 1973, 5, 829. Adkins, H.; R. Connar. J. Am. Chem. Soc. 1931, 53, 1091. Davies, R. R.; Hodgson, H. H. J. Chem. Soc. 1943, 281. Broadbent, H. S.; Slaugh, L. H.; Jarvis, N. L. J. Am. Chem. Soc. 1954, 76, 1519. Tsukinoki, T.; Tsuzuki, H. Green. Chem. 2001, 3, 37–38. Hodgson, H. H.; Whitehurst, J. S. J. Am. Chem. Soc. 1945, 202. Wang, L.; Zhou, L.; Zhang, Synlett. 1999, 1065. Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin Trans. 2001. 1. 955. Blackie, J. A.; Turner, N.J.; Wells, A. S. Tetrahedron Lett. 1997, 38, 3043, these references being incorporated by reference.